To the shock and disbelief of many, the FDA told the drug's sponsor, Sanofi's Genzyme unit, that the unusual design of the pivotal trials would not permit a clear determination of whether the drug had worked -- even though the design had been discussed beforehand with the agency and officials had allowed the studies to go forward.

The trials, you may remember, compared alemtuzumab with interferon-beta with an open-label design. Genzyme decided not to attempt to blind the patients or the personnel treating them because of the vastly different dosing regimens for the two drugs. Alemtuzumab was delivered in an initial 5-day course of infusions followed a year later with a second 3-day course. Interferon-beta was given subcutaneously three times a week.

A double-blind, double-dummy study -- always the FDA's preferred design -- would have required patients in the alemtuzumab arm to take hundreds of sham injections. Moreover, as one of the trials' leaders told MedPage Today, the side effects of each drug are very distinctive and any attempt at blinding would have failed anyway. Neurologists who conducted the examinations for efficacy outcomes were not told of treatment assignments or of patients' adverse effects.

So if this design was fundamentally flawed in the FDA's view, it raises the question: did the FDA mislead Genzyme or did the firm fail to heed warnings that the agency had sent?

At this point there is no clear answer. The FDA never comments on discussions its staff holds with drug sponsors, and Genzyme declined to comment as well, citing a pending appeal of the FDA decision.

However, I spoke with Edward Fox, MD, PhD, of Central Texas Neurology Consultants in Round Rock, Texas, who was a member of the steering committee that managed the two pivotal alemtuzumab trials. (As such, Fox has been paid by Genzyme and the interview was arranged by a company representative.)

A Double-Cross?

Fox was emphatic in blaming the FDA.

"To me, it feels like a double-cross," he said.

"They had to allow this drug to be given in these clinical trials," he pointed out, because the FDA had previously put the program on a clinical hold after one patient receiving the drug developed idiopathic thrombocytopenic purpura (ITP). In such situations, the agency carefully reviews whether the trial is important enough and is sufficiently well-designed to justify risks to additional patients.

"My opinion is that, if it was truly not going to be acceptable, if this trial design was never going to work, it should have been made public by the FDA and I should never have been able to enroll patients into the trial," Fox said. "It really is unfair to those patients to spend their time and effort to be part of those trials to be told later that their efforts had no value.

In other words, the pivotal studies should have been found unethical from the beginning if the FDA wasn't satisfied that the open-label design could produce data that would support approval.

And, Fox argued, the trials did provide such data.

"I cannot express enough how shocked I was at the FDA's opinion. I thought there would never be a question about the efficacy of this drug once the data set was out. This was overwhelmingly positive data."

In both trials, annualized relapse rates in the alemtuzumab arms were about half those seen with interferon-beta. The FDA's advisory committee voted 12-6 that effectiveness had been adequately proved.

It was less clear whether alemtuzumab was superior in terms of disability progression, and the FDA's advisory committee found that it was not proven. But Genzyme probably would have been satisfied with an approval that denied a label claim on disability.

Fox said he expected that the FDA's advisory committee would have the most concerns about the drug's safety, since a significant minority of patients developed ITP and other secondary autoimmune conditions. But, after substantial discussion, the panel voted unanimously that the adverse effects did not preclude approval.

What Next?

Immediately on receiving the FDA's complete response letter, Genzyme said it would appeal the decision. Many patients and physicians vowed to do the same.

Fox said he and other investigators in the drug's trials were drafting a letter to the FDA re-arguing their case for the appropriateness of the trial designs. He said he knew of other neurologists who were protesting the agency's decision independently, in letters to the FDA or its parent, the Department of Health and Human Services.

If those efforts fail, Genzyme's only recourse will be to conduct a new trial -- presumably with a double-blind, double-dummy design. Fox told me that such a trial would certainly be feasible, even though it would likely be no more blinded in reality than the open-label studies.

However, like other MS trials, it would need to run for at least 2 years and would cost tens of millions of dollars -- for a drug that nearly everyone outside the FDA agrees has been shown to be effective.

Striking a Nerve is a blog by John Gever for readers interested in neurology and psychiatry.

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